The Pima Indians of Arizona have the highest prevalence and incidence rate of non-insulin dependent diabetes mellitus (NIDDM) of any population in the world. We have been studying a subset of this population to determine the metabolic characteristics that predict the development of the disease, and also to determine the exact sequence of metabolic events that occur in individuals that make the transition from normal glucose tolerance to impaired glucose tolerance than on to diabetes. Our observations to date demonstrate that insulin resistance is a very strong predictor of the development of diabetes in the population. The Pimas are more insulin resistant than Caucasian subjects, and this is independent of the effect of obesity to worsen insulin resistance. Also compared to Caucasians, Pimas secrete much more insulin in response to similar degrees of insulin resistance and this is particularly true at early time points after an oral glucose load or after ingesting a standard mixed meal. Insulin resistance in the population shows strong familial aggregation. The frequency distribution of insulin action in the population is distributed trimodally, consistent with a genetic inheritance of an autosomal, co-dominantly inherited gene for insulin resistance. Studies are underway to identify this putative gene.